Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast).
Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.
Hutchinson
Mark R
MR
Department of Psychology and the Center for Neuroscience, Campus Box 345, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Lewis
Susannah S
SS
Coats
Benjamen D
BD
Skyba
David A
DA
Crysdale
Nicole Y
NY
Berkelhammer
Debra L
DL
Brzeski
Anita
A
Northcutt
Alexis
A
Vietz
Christine M
CM
Judd
Charles M
CM
Maier
Steven F
SF
Watkins
Linda R
LR
Johnson
Kirk W
KW
D000698:Analgesia / Q000523:psychology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology; D009020:Morphine / Q000009:adverse effects; D009270:Naloxone / Q000009:adverse effects; D009293:Opioid-Related Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D010098:Oxycodone / Q000009:adverse effects; D010146:Pain / Q000503:physiopathology / Q000523:psychology; D010147:Pain Measurement; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D015431:Weight Loss / Q000187:drug effects; D007212:Indolizines; D011720:Pyrazoles
D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D001993:Bronchodilator Agents; D005904:Glial Fibrillary Acidic Protein; D008911:Minocycline; D009020:Morphine; D009270:Naloxone; D010098:Oxycodone; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles